Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6–9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg · d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT1R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT1R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT1R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT1R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.
Sagittal synostosis has been successfully managed with numerous surgical techniques. Nevertheless, few data on long-term outcomes exist to justify use of one surgical technique over another. In this study, we compared children with surgically corrected sagittal synostosis to their age-matched control subjects to assess the longevity of their corrections. Furthermore, the outcomes of open repairs were compared with endoscopic repairs.Following institutional review board approval, three-dimensional photographs of patients who underwent surgical reconstruction for nonsyndromic sagittal synostosis were analyzed to determine biparietal and anterior-posterior diameter, circumference, cephalic index, cranial vault volume, cranial height, and forehead inclination. Thirteen patients who had undergone open repair, including 6 total cranial vault and 7 modified-pi reconstructions, and 6 patients who had undergone endoscopic strip craniectomy with barrel-stave osteotomies and postoperative helmeting were compared with nonsynostotic age-matched control subjects. Mean follow-up was 97.5 months after open and 48.9 months after endoscopic repair. Student t tests were used for analysis. In the second arm of this study, 33 patients who had undergone endoscopic repair were compared with the 13 patients who had undergone open repair; mean follow-up was 24.8 months after endoscopic repair. Linear regression models were used to adjust for age and sex.After comparing three-dimensional photographs of children who were more than 3 years postoperative from surgical correction for sagittal synostosis with their age-matched control subjects, no statistically significant differences were found in any of the measured parameters. In addition, no differences were detected between open reconstruction versus endoscopic repair, suggesting equivalence in final results for both procedures.
Ultrastructural observations reveal a continuous interstitial matrix connection between the endocrine and exocrine pancreas, which is lost due to fibrosis in rodent models and humans with type 2 diabetes mellitus (T2DM). Widening of the islet exocrine interface (IEI) appears to result in loss of desmosomes and adherens junctions between islet and acinar cells and is associated with hypercellularity consisting of pericytes and inflammatory cells in T2DM pancreatic tissue. Organized fibrillar collagen was closely associated with pericytes, which are known to differentiate into myofibroblasts – pancreatic stellate cells. Importantly, some pericyte cellular processes traverse both the connecting IEI and the endoacinar interstitium of the exocrine pancreas. Loss of cellular paracrine communication and extracellular matrix remodeling fibrosis in young animal models and humans may result in a dysfunctional insulino-acinar-ductal – incretin gut hormone axis resulting in pancreatic insufficiency and glucagon like peptide deficiency known to exist in prediabetes and overt T2DM in humans.
Our retrospective series shows that endoscopic and open repairs of metopic craniosynostosis are equivalent in improving hypotelorism and trigonocephaly at 1-year follow-up. Additional studies are necessary to better define minor differences in morphology, which may result from the different techniques.
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